Colorectal cancer is a disease characterized by unchecked proliferation of cells of the large intestine, including cells of the colon or rectum. Colorectal cancer tumors are believed to originate in normal mucosa. Tumorigenesis is associated with the appearance of clusters of enlarged crypts showing proliferative and biochemical abnormalities. Proliferation of the epithelial cells that carry the causative mutation or mutations can become early stage tumors characterized by high-grade dysplasia. Further growth can result in invasive growth into the muscle layers and through the bowel wall. If untreated, these tumors can spread to regional lymph nodes and then metastasize to distant sites, at which point they become largely untreatable using currently available technologies (Markowitz and Bertagnolli (2009) N. Engl. J. Med. 361(25): 2449-2460). While tumors can arise de novo, evidence indicates that approximately 60% of carcinomas originate from pre-existing adenomas (Soreide et al., (2011) Discov. Med. 12(66):393-404). Thus, the vast majority of colorectal cancer tumors can be classified as adenocarcinomas, but lymphomas and squamous cell carcinomas are also observed in a smaller subset of cases. Genetic mutations that result in carcinogenesis include mutations in members of the Wnt signaling pathway, members of the TGF-β cell signaling pathway such as TGF-β1 and SMAD family members, proteins that regulate the balance between cell proliferation and cell death such as TP53, and other proteins such as DCC (Reya and Clevers (2005) Nature 434(7035):843-850; Baker et al., (1989) Science 244:217-221; Markowitz and Bertagnolli, supra). Abnormal PI3K/Akt activation and downstream mTOR signaling are associated with colorectal cancer tumorigenesis (Rychahou et al., (2006) Ann. Surg. 243(6):833-842). High levels of EGFR expression have also been observed in colon cancer cell lines and are correlated with colorectal cancer tumor progression (Ciardiello et al., (1991) Proc. Natl. Acad. Sci. USA 88(17):7792-7796). Beyond familial and genetic factors, risk factors for colorectal cancer may include low levels of physical activity, alcohol consumption, high dietary intake of fat and meat and low intake of fiber and vegetables. Symptoms of colorectal cancer typically include rectal bleeding, anemia, constipation, blood in the stool, weight loss, fever, loss of appetite, and nausea or vomiting.
Colorectal cancer is the second most common form of cancer among American male and female survivors of cancer (Siegel et al., (2012) CA Cancer J. Clin. 62(4):220-41). Additionally, colorectal cancer is among the top three most common causes of cancer death in the Western world (Soreide et al., (2011) Discov. Med. 12(66):393-404). The more recent adaptation of many Asian countries to a Western lifestyle has also resulted in a significant increase in colorectal cancer in those populations (Yang et al., (2011) Dig. Surg. 28(5-6):379-385). In 2012, it is estimated that there were 1.2 million individuals in the United States living with a previous diagnosis of colorectal cancer. For the same year, it was predicted that an additional 143,460 would be diagnosed with the disease. The median age at diagnosis of colorectal cancer is 68 years for males and 72 years for females (Howlader et al., (2011) SEER Cancer Statistics Review, 1975-2008. Bethesda, Md.: National Cancer Institute). While incidence of colorectal cancer is not rare in elderly adults, only 59.1% of individuals over the age of 50 receive colorectal cancer screening according to guidelines (American Cancer Society (2012) Cancer Prevention & Early Detection Facts & Figures. Atlanta, Ga.: American Cancer Society). This lack of early detection results in only 39% of patients being diagnosed when the cancer has not progressed past a local stage (Howlader et al., supra). Given the increasing number of patients suffering from colorectal cancer, there is a need for development of robust treatment methods, especially for the large number of patients who are not identified by early screening.